LRP12 is an 859-residue type-I single-pass plasma-membrane protein of the low-density-lipoprotein-receptor-related family. Its extracellular region contains two CUB domains and five LDL-receptor class A repeats, followed by one transmembrane helix and a long cytoplasmic tail. The tail binds Ξ±4 integrins and interferes with talin engagement, restraining integrin activation and balancing nascent-adhesion turnover and cell migration; it also interacts with RACK1, NMRK2/MIBP, and ZFYVE9/SARA. Mouse developmental studies link Lrp12 to neuronal arborization, migration, and cortical lamination. Two named human protein isoforms differ by a short N-terminal deletion. Noncoding CGG-repeat expansions in the LRP12 5-prime untranslated region cause oculopharyngodistal myopathy 1 and, at shorter pathogenic repeat lengths, amyotrophic lateral sclerosis 28.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: LRP12 is a single-pass membrane protein, and independent human evidence places it at the plasma membrane. Reason: Plasma-membrane activity is conserved across the heterogeneous LDLR-family IBA set and is independently supported for human LRP12. The target appearing in its own donor set is expected evidence grounding, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0030706 SUPPORTS TRANSFER FB:FBgn0051092 SUPPORTS TRANSFER MGI:MGI:1340044 SUPPORTS TRANSFER MGI:MGI:1860083 SUPPORTS TRANSFER MGI:MGI:2138856 SUPPORTS TRANSFER MGI:MGI:2442252 SUPPORTS TRANSFER MGI:MGI:96765 SUPPORTS TRANSFER MGI:MGI:96828 SUPPORTS TRANSFER PANTHER:PTN002557696 SUPPORTS TRANSFER RGD:2998 SUPPORTS TRANSFER RGD:619731 SUPPORTS TRANSFER RGD:727887 SUPPORTS TRANSFER UniProtKB:E1BGJ0 SUPPORTS TRANSFER UniProtKB:P01130 SUPPORTS TRANSFER UniProtKB:P01131 SUPPORTS TRANSFER UniProtKB:P98155 SUPPORTS TRANSFER UniProtKB:Q07954 SUPPORTS TRANSFER UniProtKB:Q14114 SUPPORTS TRANSFER UniProtKB:Q86YD5 SUPPORTS TRANSFER UniProtKB:Q9NPF0 SUPPORTS TRANSFER UniProtKB:Q9Y561 SUPPORTS TRANSFER UniProtKB:Q9Y5Q5 SUPPORTS TRANSFER WB:WBGene00003071 SUPPORTS TRANSFER WB:WBGene00015083 SUPPORTS TRANSFER WB:WBGene00019811 SUPPORTS TRANSFER |
| GO:0001764 neuron migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic annotation links LRP12 to neuronal migration, a developmental phenotype tested by LRP12 knockdown in mouse cortex. Reason: Mouse cortical knockdown causes neuronal malpositioning, making this a plausible conserved outcome, but neuronal migration is tissue- and stage-specific rather than LRP12βs defining molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00089626 SUPPORTS TRANSFER |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: The UniProt subcellular-location mapping correctly identifies LRP12 as membrane-associated but is less specific than direct plasma-membrane evidence. Reason: LRP12 is a single-pass type-I protein directly localized to the plasma membrane; GO:0005886 is more informative than the generic membrane term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0162 SUPPORTS TRANSFER Proposed replacements: plasma membrane |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000108 | REMOVE | Summary: This logical inference derives vesicle-mediated transport from the older low-density-lipoprotein-particle receptor assertion. Reason: The inference depends solely on GO:0005041, which this review removes because no LDL-particle binding or uptake assay supports it. The cited LRP12 work identifies LDLR-family motifs but does not independently demonstrate cargo internalization or vesicular flux, so the derived vesicle-mediated-transport assertion should also be removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: GO:0005041 SOURCE WEAK OR INFERRED |
| GO:0031175 neuron projection development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Electronic annotation links LRP12 to neuronal projection development, consistent with knockdown-induced arborization defects. Reason: Impaired neuronal arborization after mouse Lrp12 knockdown supports a conserved developmental role, but this is a context-specific downstream phenotype rather than a core molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026765 SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | KEEP AS NON CORE | Summary: The normalized IPI row combines six ordered partners detected for the LRP12 cytoplasmic tail, including RACK1, ZFYVE9, NMRK2, SNAPIN, ACTN2, and MYOT. Reason: The yeast two-hybrid and interaction records support multiple physical associations, but no single more-specific current GO binding term describes the heterogeneous partner set. Generic protein binding is retained as non-core rather than used to define LRP12 function. Supporting Evidence: PMID:12809483 Use of the yeast two-hybrid system to identify proteins that associate with ST7's cytoplasmic domain revealed that this domain interacts with three proteins involved in signal transduction and/or endocytosis, viz., receptor for activated protein C kinase 1 (RACK1), muscle integrin binding protein (MIBP), and SMAD anchor for receptor activation (SARA), suggesting that ST7, like other proteins in the LDLR superfamily, functions in these two pathways. |
| GO:0005178 integrin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfers Ξ±4-integrin binding from experimentally annotated mouse Lrp12. Reason: The source is the exact mouse ortholog, for which direct interaction evidence supports Lrp12 binding to Ξ±4 integrins; the receptorβs conserved cytoplasmic tail makes this transfer biologically coherent and functionally specific. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUJ9 SUPPORTS TRANSFER ensembl:ENSMUSP00000022916 SUPPORTS TRANSFER |
| GO:0001764 neuron migration | IDA PMID:26639854 LRP12 silencing during brain development results in cortical... | KEEP AS NON CORE | Summary: LRP12 silencing in the developing mouse cortex caused upper-layer neuron malpositioning. Reason: The experimental phenotype supports an upstream role in neuronal migration, but it is a mouse developmental outcome rather than LRP12βs core molecular activity. Supporting Evidence: PMID:26639854 In vivo ablation of LRP12 by intraventricularly in utero electroporated shRNAs elicits cortical maldevelopment, i.e. aberrant lamination by malpositioning of upper cortical layer neurons. |
| GO:0031175 neuron projection development | IDA PMID:26639854 LRP12 silencing during brain development results in cortical... | KEEP AS NON CORE | Summary: LRP12 knockdown in primary neurons impaired neuronal arborization. Reason: The direct knockdown phenotype supports a role in neuron projection development, but this context-specific developmental output is non-core. Supporting Evidence: PMID:26639854 In vitro knockdown of LRP12 in primary neurons results in impaired neuronal arborization. |
| GO:0005886 plasma membrane | IDA PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | ACCEPT | Summary: Experimental curation places human LRP12 at the plasma membrane, consistent with its type-I transmembrane topology. Reason: The plasma membrane is the functionally relevant site for this single-pass surface protein, and the cached abstract plus curated UniProt record independently support its transmembrane receptor topology. Supporting Evidence: PMID:12809483 In 1997, McCormick and co-workers identified a novel putative tumor suppressor gene, designated ST7, encoding a unique protein with transmembrane receptor characteristics [Qing et al. (1999) Oncogene 18, 335-342]. PMID:9927190 Molecular cloning of a near full-length cDNA revealed that the novel gene encodes a putative transmembrane protein composed of 859 amino acids: the 492 N-terminal amino acids including a fivefold cysteine-rich repeat of 40 amino acids homologous to the ligand binding repeat of the known low density lipoprotein receptor, a 24 hydrophobic amino acid stretch spanning the plasma membrane, and a C-terminal domain of 343 residues. |
| GO:0005041 low-density lipoprotein particle receptor activity | NAS PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | REMOVE | Summary: The low-density-lipoprotein-particle receptor assertion is based on LDLR-family resemblance rather than a demonstrated LDL-binding and uptake assay. Reason: GO:0005041 requires binding and endocytic delivery of LDL particles. The paper establishes family membership and cytoplasmic motifs but reports no LDL ligand-binding or internalization experiment for LRP12, and the unsupported NAS assertion is the premise for the removed vesicle-transport inference. Supporting Evidence: PMID:12809483 These results strongly suggested that ST7 was also a novel member of the low-density lipoprotein receptor superfamily. |
| GO:0006897 endocytosis | NAS PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | MARK AS OVER ANNOTATED | Summary: The endocytosis assertion was inferred from family membership and cytoplasmic motifs rather than measured cargo uptake. Reason: The paper explicitly set out to test whether LRP12 might function in endocytosis but reports motif analysis and protein interactions, not endocytic flux. Unlike the machine-derived GO:0016192 inference from a rejected premise, this NAS reflects the authors' stated endocytosis hypothesis; it is therefore retained as over-annotated rather than removed, while still exceeding the accessible experimental evidence. Supporting Evidence: PMID:12809483 To evaluate the relationship of ST7 to the LDLR superfamily proteins and to determine whether ST7 may function in endocytosis and/or signal transduction, we used proteomic tools to analyze the functional motifs present in the protein. |
| GO:0007165 signal transduction | NAS PMID:12809483 ST7 is a novel low-density lipoprotein receptor-related prot... | KEEP AS NON CORE | Summary: LRP12βs cytoplasmic tail binds several proteins associated with signaling pathways, but the annotation is broad. Reason: Direct interaction data make participation in signaling biologically plausible, while the 2003 study does not define a ligand, pathway output, or causal signaling response. The generic process is retained conservatively as non-core. Supporting Evidence: PMID:12809483 Use of the yeast two-hybrid system to identify proteins that associate with ST7's cytoplasmic domain revealed that this domain interacts with three proteins involved in signal transduction and/or endocytosis, viz., receptor for activated protein C kinase 1 (RACK1), muscle integrin binding protein (MIBP), and SMAD anchor for receptor activation (SARA), suggesting that ST7, like other proteins in the LDLR superfamily, functions in these two pathways. |
| GO:0016020 membrane | NAS PMID:9927190 Cloning and characterization of a novel gene encoding a puta... | MODIFY | Summary: The original human cDNA encodes a transmembrane protein with a hydrophobic segment spanning the plasma membrane. Reason: The experimentally described topology supports the more informative plasma-membrane term rather than generic membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:9927190 Molecular cloning of a near full-length cDNA revealed that the novel gene encodes a putative transmembrane protein composed of 859 amino acids: the 492 N-terminal amino acids including a fivefold cysteine-rich repeat of 40 amino acids homologous to the ligand binding repeat of the known low density lipoprotein receptor, a 24 hydrophobic amino acid stretch spanning the plasma membrane, and a C-terminal domain of 343 residues. |
| GO:0040008 regulation of growth | NAS PMID:9927190 Cloning and characterization of a novel gene encoding a puta... | MARK AS OVER ANNOTATED | Summary: LRP12 was downregulated in transformed and tumor-derived cell lines, but growth regulation was not directly assayed. Reason: Differential expression and candidate-tumor-suppressor framing do not establish that LRP12 regulates organismal or cellular growth. The cached abstract describes this as an initial characterization and a possible role in transformation. Supporting Evidence: PMID:9927190 These studies are a first step in characterizing a novel putative receptor protein, whose expression is downregulated in some malignantly transformed cells, and which may play an important role in the transformation process of these cells. |
| GO:0033624 negative regulation of integrin activation | ISO PMID:37330909 LRP12 is an endogenous transmembrane inactivator of Ξ±4 integ... | NEW | Summary: Human LRP12 is proposed to negatively regulate integrin activation from the experimentally annotated mouse ortholog Q8BUJ9. Reason: PMID:37330909 reports that LRP12 directly binds the Ξ±4-integrin cytoplasmic tail and prevents talin engagement, thereby maintaining the inactive integrin state. The cached abstract does not identify the organism or constructs used for those molecular assays. GO provenance places the experimental integrin-binding annotation on mouse Q8BUJ9 and transfers it to human LRP12 by Ensembl Compara; GO:0033624 captures the immediate regulatory consequence without asserting unverified assay details or generalizing beyond Ξ±4 integrins. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BUJ9 SUPPORTS TRANSFER Supporting Evidence: PMID:37330909 The LRP12 cytoplasmic domain directly binds to the integrin Ξ±4 cytoplasmic tail and inhibits talin binding to the Ξ² subunit, thus keeping integrin inactive. |
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Download this section (compressed HTML)Q: Which endogenous human Ξ±4-integrin heterodimers (Ξ±4Ξ²1 versus Ξ±4Ξ²7) and cell types are regulated by LRP12?
Q: Does the extracellular LDLR-like region bind a physiological ligand or cargo, and does ligand engagement modulate LRP12-integrin coupling or internalization?
Q: Are both curated human LRP12 isoforms translated, surface-delivered, and competent for Ξ±4-integrin regulation in the same tissues?
Q: Are mouse neuronal-development phenotypes caused by the Ξ±4-integrin mechanism, a distinct LRP12 signaling pathway, or both?
Q: Are the reported ACTN2 and MYOT tail interactions reproducible in muscle, and do they inform normal LRP12 biology independently of the noncoding repeat-mediated pathology in OPDM1?
Experiment: Generate isogenic LRP12-null human Ξ±4-integrin-expressing primary or lineage-relevant cells, rescue with expression-matched wild-type LRP12 or mapped interface mutants, and quantify LRP12-Ξ±4 proximity, activation-specific integrin epitopes, talin recruitment, nascent-adhesion turnover, adhesion, and migration.
Hypothesis: Endogenous human LRP12 restrains Ξ±4-integrin activation through direct cytoplasmic-tail binding that excludes talin.
Type: endogenous receptor-integrin mechanism and rescue study
Experiment: Perform unbiased native ectodomain ligand capture and cell-surface binding screens, validate candidates biophysically, and use pulse-chase imaging to distinguish binding, internalization, recycling, and degradation; include LDL particles and endocytosis-defective tail mutants as explicit controls.
Hypothesis: LRP12 has a specific extracellular ligand that regulates its surface organization or cargo uptake rather than a generic LDL-receptor activity.
Type: ligand discovery and quantitative trafficking assay
Experiment: Establish isoform-resolved transcript and targeted-proteomic measurements in human tissues, engineer each isoform at the endogenous locus, and compare signal-peptide processing, glycosylation, surface abundance, Ξ±4-integrin inhibition, ligand binding, and uptake at matched expression.
Hypothesis: The 19-residue N-terminal deletion in isoform 2 changes processing or surface delivery and thereby alters LRP12 function.
Type: endogenous isoform-resolved functional comparison
Experiment: Use LRP12-null human neural progenitors and cortical organoids rescued with wild-type or Ξ±4-binding-deficient LRP12; quantify integrin activation, adhesion dynamics, neurite branching, cell migration, and laminar organization while testing Ξ±4-integrin epistasis.
Hypothesis: LRP12-dependent human neural migration and arborization require its Ξ±4-integrin inhibitory interface.
Type: human neural organoid mechanism and epistasis study
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The species and constructs used for the Ξ±4-integrin molecular assays, and independent curated experimental confirmation on human LRP12, remain unresolved from the accessible evidence.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: PMID:37330909 establishes LRP12 tail binding, talin exclusion, and integrin inactivation, but its abstract does not state the organism or constructs for those assays. GO currently records experimental integrin binding on mouse Q8BUJ9 and an exact-ortholog IEA on human LRP12; this provenance does not establish what every experiment in the paper tested.
Significance: Species- and construct-resolved evidence is required to define the physiological human receptor-integrin pair, relevant cell types, and conservation of the talin-exclusion mechanism.
What would resolve it: Test endogenous LRP12-Ξ±4 proximity and binding in human Ξ±4-integrin-expressing primary cells, perturb LRP12, and rescue with expression-matched wild-type or Ξ±4-tail-interface mutants while measuring integrin conformation, talin recruitment, adhesion turnover, and migration.
Provenance (the field's own admissions):
Gap: The physiological extracellular ligand and any cargo-internalization function of LRP12 remain unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human studies establish LDLR-family architecture, endocytic/signaling motifs, and several cytoplasmic-tail interactions. They do not demonstrate LDL-particle binding, a defined extracellular ligand, receptor-mediated cargo uptake, or endocytic flux.
Significance: Identifying extracellular partners is necessary to determine whether LRP12 couples ligand recognition to integrin regulation, signaling, or trafficking rather than merely sharing LDLR-family architecture.
What would resolve it: Use native ectodomain capture and quantitative surface-interaction screens followed by purified binding and internalization assays; compare candidate ligands and LDL particles with controls that separate surface binding from productive uptake.
Provenance (the field's own admissions):
Gap: Functional differences between the two curated human LRP12 isoforms are unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: UniProt curates isoform 1 as the displayed sequence and isoform 2 with a 19-residue N-terminal deletion, but the reviewed integrin, neuronal, trafficking, and cancer studies do not establish isoform-specific activity or endogenous protein abundance.
Significance: The N-terminal difference may affect signal-peptide processing, surface delivery, or extracellular interactions, so canonical-product findings cannot automatically be assigned to both proteoforms.
What would resolve it: Resolve isoform transcripts and proteins across human tissues, then compare processing, surface abundance, Ξ±4-integrin regulation, extracellular-partner binding, and internalization using expression-matched and endogenous isoform perturbations.
Provenance (the field's own admissions):
Gap: The mechanism connecting Lrp12 to neuronal arborization, migration, and cortical lamination is not defined and has not been tested directly in human neural cells.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Loss-of-function phenotypes are from mouse primary neurons and embryonic cortex. The reporter study maps an Lrp12-positive preplate population and Reelin-dependent patterning but does not establish Lrp12 as a Reelin receptor or show that Ξ±4-integrin regulation causes the neuronal outcomes.
Significance: Connecting the receptor's molecular activity to neural phenotypes would distinguish a conserved cell-adhesion mechanism from a separate developmental pathway.
What would resolve it: Perturb LRP12 in human neural progenitors and cortical organoids, rescue with wild-type and Ξ±4-binding-deficient variants, and measure integrin activation, adhesion dynamics, neurite architecture, migration, and laminar positioning.
Provenance (the field's own admissions):
Gap: No experimental structure defines full-length LRP12 or its complex with Ξ±4 integrin.
OPEN BIOLOGY
What is known: The reviewed record contains an AlphaFold prediction but no experimental PDB cross-reference. The relative arrangement of the extracellular repeats, transmembrane helices, cytoplasmic tails, and talin-competitive interface in a membrane is therefore unknown.
Significance: Structural definition would reveal how a single-pass receptor recognizes an integrin tail and whether extracellular or membrane organization regulates that interaction.
What would resolve it: Reconstitute full-length human LRP12 with a defined Ξ±4-integrin heterodimer in a membrane and combine cryo-EM or integrative structural analysis with interface mutagenesis, talin competition, and functional rescue.
Provenance (the field's own admissions):
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